Modulating macrophages to improve drug delivery and immunotherapy
short project description
Hepatocellular carcinoma (HCC) commonly arises as a consequence of chronic liver damage, resulting in inflammatory responses. Treatment options are limited. Immunotherapies may yield promising results in patients, but objective response rates are <30%. In previous studies, we identified infiltrating inflammatory monocytes as drivers of liver fibrosis and pathogenic microenvironmental changes (1). When the infiltration of these cells was blocked by an inhibitor of the chemokine CCL2, monocyte recruitment was reduced, angiogenesis attenuated and fibrogenesis delayed (2). In ongoing studies, we also already showed that blocking monocyte infiltration in a combined fibrosis-HCC model in mice reduced tumor load and tumor vascularization, and affected the tumor-associated macrophage population without inhibiting tumor-promoting myeloid derived suppressor cells.
We hypothesize that modulating macrophages can enhance tumor-targeted drug delivery and the efficacy of immunotherapy. Specific aims are: i. to characterize macrophage heterogeneity in a fibrosis-HCC model; ii. to modulate macrophage infiltration and polarisation, in order to thereby reduce microenvironmental heterogeneity and pathogenic angiogenesis; and iii. to explore the consequences of macrophage modulation for improving tumor-targeted drug delivery and for enhancing the efficacy of antibody-based immune checkpoint inhibitor therapies.
Krenkel O, Tacke F: Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017, 17(5):306-321.
Ehling J, Bartneck M, Wei X, Gremse F, Fech V, Mockel D, Baeck C, Hittatiya K, Eulberg D, Luedde T, Kiessling F, Trautwein C, Lammers T, Tacke F: CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014, 63(12):1960-1971.
Bartneck M, Scheyda KM, Warzecha KT, Rizzo LY, Hittatiya K, Luedde T, Storm G, Trautwein C, Lammers T, Tacke F: Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. Biomaterials 2015, 37:367-382.
Schneider C, Teufel A, Yevsa T, Staib F, Hohmeyer A, Walenda G, Zimmermann HW, Vucur M, Huss S, Gassler N, Wasmuth HE, Lira SA, Zender L, Luedde T, Trautwein C, Tacke F: Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 2012, 61(12):1733-1743.
Ergen C, Heymann F, Al Rawashdeh W, Gremse F, Bartneck M, Panzer U, Pola R, Pechar M, Storm G, Mohr N, Barz M, Zentel R, Kiessling F, Trautwein C, Lammers T, Tacke F: Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles. Biomaterials 2017, 114:106-120.